The glycolytic enzyme PFKFB3 determines bone marrow endothelial progenitor cell damage after chemotherapy and irradiation.

Abstract

Bone marrow (BM) endothelial progenitor cell (EPC) damage of unknown mechanism delays the repair of endothelial cells (EC) and recovery of hematopoiesis after chemo-radiotherapy. We found increased levels of the glycolytic enzyme PFKFB3 in the damaged BM EPC of patients with poor graft function, a clinical model of EPC damage-associated poor hematopoiesis after allogeneic hematopoietic stem cell transplantation. Moreover, in vitro the glycolysis inhibitor 3-(3-pyridinyl)- 1-(4-pyridinyl)-2-propen-1-one (3PO) alleviated the damaged BM EPC from patients with poor graft function. Consistently, PFKFB3 overexpression triggered BM EPC damage after 5-fluorouracil treatment and impaired hematopoiesis-supporting ability in vitro. Mechanistically, PFKFB3 facilitated pro-apoptotic transcription factor FOXO3A and expression of its downstream genes, including p21, p27, and FAS, after 5-fluorouracil treatment in vitro. Moreover, PFKFB3 induced activation of NF-κB and expression of its downstream adhesion molecule E-selectin, while it reduced hematopoietic factor SDF-1 expression, which could be rescued by FOXO3A silencing. High expression of PFKFB3 was found in damaged BM EC of murine models of chemo-radiotherapy-induced myelosuppression. Furthermore, a murine model of BM EC-specific PFKFB3 overexpression demonstrated that PFKFB3 aggravated BM EC damage, and impaired the recovery of hematopoiesis after chemotherapy in vivo, effects which could be mitigated by 3PO, indicating a critical role of PFKFB3 in regulating BM EC damage. Clinically, PFKFB3-induced FOXO3A expression and NF-κB activation were confirmed to contribute to the damaged BM EPC of patients with acute leukemia after chemotherapy. 3PO repaired the damaged BM EPC by reducing FOXO3A expression and phospho-NF-κB p65 in patients after chemotherapy. In summary, our results reveal a critical role of PFKFB3 in triggering BM EPC damage and indicate that endothelial-PFKFB3 may be a potential therapeutic target for myelosuppressive injury.

• Authors: Zhong-Shi Lyu, Shu-Qian Tang, Tong Xing, Yang Zhou, Meng Lv, Hai-Xia Fu, Yu Wang, Lan-Ping Xu, Xiao-Hui Zhang, Hsiang-Ying Lee, Yuan Kong, Xiao-Jun Huang
• Journal: Haematologica (Haematologica) Vol. 107 Issue 10 Pg. 2365-2380 (10 01 2022) ISSN: 1592-8721 [Electronic] Italy
• PMID: 35354250 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• E-Selectin
• Fluorouracil
• NF-kappa B
• PFKFB3 protein, human
• Phosphofructokinase-2

Topics

• Animals
• Humans
• Mice
• Bone Marrow (metabolism)
• E-Selectin (metabolism)
• Endothelial Progenitor Cells (metabolism)
• Fluorouracil (pharmacology)
• Glycolysis
• NF-kappa B (metabolism)
• Phosphofructokinase-2 (genetics, metabolism)